scholarly journals Tumor mutational landscape is a record of the pre-malignant state

2019 ◽  
Author(s):  
Kirsten Kübler ◽  
Rosa Karlić ◽  
Nicholas J. Haradhvala ◽  
Kyungsik Ha ◽  
Jaegil Kim ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Dna Sequences ◽  
Chromatin Structure ◽  
Somatic Mutations ◽  
Major Influence ◽  
Cell Of Origin ◽  
Regional Patterns ◽  
Cancer Subtypes ◽  
Mutational Landscape ◽  
Cancer Types

ABSTRACTChromatin structure has a major influence on the cell-specific density of somatic mutations along the cancer genome. Here, we present a pan-cancer study in which we searched for the putative cancer cell-of-origin of 2,550 whole genomes, representing 32 cancer types by matching their mutational landscape to the regional patterns of chromatin modifications ascertained in 104 normal tissue types. We found that, in almost all cancer types, the cell-of-origin can be predicted solely from their DNA sequences. Our analysis validated the hypothesis that high-grade serous ovarian cancer originates in the fallopian tube and identified distinct origins of breast cancer subtypes. We also demonstrated that the technique is equally capable of identifying the cell-of-origin for a series of 2,044 metastatic samples from 22 of the tumor types available as primaries. Moreover, cancer drivers, whether inherited or acquired, reside in active chromatin regions in the respective cell-of-origin. Taken together, our findings highlight that many somatic mutations accumulate while the chromatin structure of the cell-of-origin is maintained and that this historical record, captured in the DNA, can be used to identify the often elusive cancer cell-of-origin.

Abstract 2727: The premalignant state captured in the landscape of somatic mutations can reveal the cancer cell-of-origin

2019 ◽  
Author(s):  
Kirsten Kubler ◽  
Rosa Karlic ◽  
Nicholas J. Haradhvala ◽  
Kyungsik Ha ◽  
Jaegil Kim ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Somatic Mutations ◽  
Cell Of Origin

Abstract 2727: The premalignant state captured in the landscape of somatic mutations can reveal the cancer cell-of-origin

2019 ◽  
Author(s):  
Kirsten Kubler ◽  
Rosa Karlic ◽  
Nicholas J. Haradhvala ◽  
Kyungsik Ha ◽  
Jaegil Kim ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Somatic Mutations ◽  
Cell Of Origin

scholarly journals Pan-Cancer Molecular Patterns and Biological Implications Associated with a Tumor-Specific Molecular Signature

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 45
Author(s):  
Darío Rocha ◽  
Iris A. García ◽  
Aldana González Montoro ◽  
Andrea Llera ◽  
Laura Prato ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Uncertainty Assessment ◽  
Cell Cycle Checkpoints ◽  
Molecular Signature ◽  
Cancer Subtypes ◽  
United States Food ◽  
Cancer Types ◽  
Molecular Patterns ◽  
Pan Cancer

Studying tissue-independent components of cancer and defining pan-cancer subtypes could be addressed using tissue-specific molecular signatures if classification errors are controlled. Since PAM50 is a well-known, United States Food and Drug Administration (FDA)-approved and commercially available breast cancer signature, we applied it with uncertainty assessment to classify tumor samples from over 33 cancer types, discarded unassigned samples, and studied the emerging tumor-agnostic molecular patterns. The percentage of unassigned samples ranged between 55.5% and 86.9% in non-breast tissues, and gene set analysis suggested that the remaining samples could be grouped into two classes (named C1 and C2) regardless of the tissue. The C2 class was more dedifferentiated, more proliferative, with higher centrosome amplification, and potentially more TP53 and RB1 mutations. We identified 28 gene sets and 95 genes mainly associated with cell-cycle progression, cell-cycle checkpoints, and DNA damage that were consistently exacerbated in the C2 class. In some cancer types, the C1/C2 classification was associated with survival and drug sensitivity, and modulated the prognostic meaning of the immune infiltrate. Our results suggest that PAM50 could be repurposed for a pan-cancer context when paired with uncertainty assessment, resulting in two classes with molecular, biological, and clinical implications.

scholarly journals Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

2018 ◽  
Vol 116 (2) ◽  
pp. 619-624 ◽  
Author(s):  
Charles Li ◽  
Elena Bonazzoli ◽  
Stefania Bellone ◽  
Jungmin Choi ◽  
Weilai Dong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Somatic Mutations ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Metastatic Tumors ◽  
Driver Genes ◽  
Primary Tumors ◽  
Mutational Landscape ◽  
Recurrent Tumors ◽  
Bet Inhibitors

Ovarian cancer remains the most lethal gynecologic malignancy. We analyzed the mutational landscape of 64 primary, 41 metastatic, and 17 recurrent fresh-frozen tumors from 77 patients along with matched normal DNA, by whole-exome sequencing (WES). We also sequenced 13 pairs of synchronous bilateral ovarian cancer (SBOC) to evaluate the evolutionary history. Lastly, to search for therapeutic targets, we evaluated the activity of the Bromodomain and Extra-Terminal motif (BET) inhibitor GS-626510 on primary tumors and xenografts harboring c-MYC amplifications. In line with previous studies, the large majority of germline and somatic mutations were found in BRCA1/2 (21%) and TP53 (86%) genes, respectively. Among mutations in known cancer driver genes, 77% were transmitted from primary tumors to metastatic tumors, and 80% from primary to recurrent tumors, indicating that driver mutations are commonly retained during ovarian cancer evolution. Importantly, the number, mutation spectra, and signatures in matched primary–metastatic tumors were extremely similar, suggesting transcoelomic metastases as an early dissemination process using preexisting metastatic ability rather than an evolution model. Similarly, comparison of SBOC showed extensive sharing of somatic mutations, unequivocally indicating a common ancestry in all cases. Among the 17 patients with matched tumors, four patients gained PIK3CA amplifications and two patients gained c-MYC amplifications in the recurrent tumors, with no loss of amplification or gain of deletions. Primary cell lines and xenografts derived from chemotherapy-resistant tumors demonstrated sensitivity to JQ1 and GS-626510 (P = 0.01), suggesting that oral BET inhibitors represent a class of personalized therapeutics in patients harboring recurrent/chemotherapy-resistant disease.

scholarly journals Dissecting Human Antibody Responses: Useful, Basic, and Surprising Findings

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-49-SCI-49
Author(s):  
Antonio Lanzavecchia
Keyword(s):  
B Cell ◽  
Dna Sequences ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Somatic Mutations ◽  
Vaccine Design ◽  
Human Memory ◽  
Affinity Maturation ◽  
Effective Vaccine ◽  
Human Antibody

Abstract We use cell culture-based high-throughput methods to interrogate human memory B cell and plasma cell repertoires and to isolate antibodies selected on the basis of their neutralizing potency and breadth. Relevant examples are antibodies that neutralize all influenza A viruses or even four paramyxoviruses. By targeting conserved structures, these broadly neutralizing antibodies are less prone to select escape mutants and are promising candidates for prophylaxis and therapy of infections, as well as tools for vaccine design. The value of a target-agnostic approach to vaccine design is illustrated by our discovery of extremely potent antibodies that neutralize human cytomegalovirus, which led to the identification of their viral ligand, a pentameric complex that was then produced and tested as an effective vaccine. By reconstructing the genealogy trees of specific B cell clones, we investigate the role of somatic mutations in affinity maturation and in generation of antibody variants with broader or different specificity. Somatic mutations can also generate autoantibodies, as found in patients with pemphigus and autoimmune pulmonary alveolar proteinosis. Recently, while searching for antibodies that broadly react with malaria variant antigens, we discovered a new mechanism of antibody diversification, which relies on templated insertions of genomic DNA sequences into immunoglobulin genes, followed by somatic mutations. Disclosures Lanzavecchia: Humabs SA: Equity Ownership, Research Funding.

scholarly journals The autophagy initiating kinase ULK1 is required for pancreatic cancer cell growth and survival

2021 ◽  
Author(s):  
Reuben J Shaw ◽  
Sonja N Brun ◽  
Jan Lumibao ◽  
Allison Limpert ◽  
Huiyu Ren ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Cancer Therapeutics ◽  
Ductal Adenocarcinoma ◽  
Cancer Cell Growth ◽  
Serine Threonine Kinase ◽  
Growth And Survival ◽  
Cancer Subtypes ◽  
Autophagy Induction ◽  
Autophagy Pathway ◽  
The Impact

Amongst cancer subtypes, pancreatic ductal adenocarcinoma (PDA) has been demonstrated to be most sensitive to autophagy inhibition, which may be due to unique metabolic rewiring in these cells. The serine/threonine kinase ULK1 forms the catalytic center of a complex mediating the first biochemical step of autophagy. ULK1 directly recieves signals from mTORC1 and AMPK to trigger autophagy under stress and nutrient poor conditions. Studies in genetic engineered mouse models of cancer have revealed that deletion of core downstream autophagy genes (ATG5, ATG7) at the time of tumor iniation leads to a profound block in tumor progression leading to the development of autophagy inhibitors as cancer therapeutics. However, most preclinical studies and all clinical studies have relied on non-specific lysomotropic agents such as chloroquine and its derivatives, whose toxicity and off-target issues preclude further clinical development and which do not represent the impact of solely biochemically disrupting the autophagy pathway. Furthermore, druggable targets in the core autophagy pathway are quite limited, with ULK1 and ULK2 representing the only protein kinases in the pathway. Here we explore the genetic requirement for ULK1 and ULK2 in human PDA cancer cell lines and xenografts, and take advantage of new small molecule ULK1 inhibitors to demonstrate that ULK inhibition can overcome autophagy induction triggered by PDA therapeutics including chemotherapy and MEK inhibition. Finally we show that ULK inhibitors increase MHC Class I in PDA cells, suggestion a potential therapeutic avenue for such agents in combination with checkpoint immunotherapy.

Serum stimulation of the c-fos enhancer induces reversible changes in c-fos chromatin structure

1990 ◽  
Vol 10 (3) ◽  
pp. 1126-1133
Author(s):  
J L Feng ◽  
B Villeponteau
Keyword(s):  
Growth Factors ◽  
Dna Sequences ◽  
Chromatin Structure ◽  
Transcriptional Activity ◽  
Dnase I ◽  
Enhancer Activity ◽  
Serum Stimulation ◽  
Fos Protein ◽  
Dnase I Sensitivity ◽  
Stimulation Of

Transcription of the proto-oncogene c-fos is known to be activated by growth factors in serum and subsequently repressed by the Fos protein. We show that generalized DNase I sensitivity of c-fos chromatin correlates closely with enhancer activity during induction, repression, and superinduction of the c-fos gene. Within 90 s of serum stimulation, proximal DNA sequences on both sides of the enhancer exhibit increased DNase I sensitivity. Within 5 min, elevated DNase I sensitivity spreads to chromatin at the distal 3' end of the c-fos gene. These results suggest that an open state of chromatin is propagated in both directions from the enhancer. The induced alterations in chromatin structure precede the increased transcriptional activity of the c-fos gene, suggesting that these changes in chromatin structure potentiate transcription.

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